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Gold drug auranofin restricts the viral reservoir in the monkey AIDS model and induces containment of viral load following ART suspension

Lewis, Mark G.a,*; DaFonseca, Sandrinab,*; Chomont, Nicolasb; Palamara, Anna T.c,d; Tardugno, Mariae; Mai, Antonelloe; Collins, Matta; Wagner, Wendeline L.a; Yalley-Ogunro, Jakea; Greenhouse, Jacka; Chirullo, Barbaraf; Norelli, Sandrof; Garaci, Enricof; Savarino, Andreaf

doi: 10.1097/QAD.0b013e328347bd77
Basic Science

Objectives: A small pool of long-lived memory CD4+ T cells harboring the retroviral genome is one main obstacle to HIV eradication. We tested the impact of the gold compound, auranofin, on phenotype and viability of CD4+ T cells in vitro, and on persistence of lentiviral reservoir cells in vivo.

Design: In-vitro and in-vivo study. The pro-differentiating effect of auranofin was investigated in human primary CD4+ T cells, and its capacity to deplete the viral DNA (vDNA) reservoir was tested in a pilot study involving six SIVmac251-infected macaques with viral loads stably suppressed by antiretroviral therapy (ART) (tenofovir/emtricitabine/raltegravir). The study was then amplified by intensifying ART using darunavir/r and including controls under intensified ART alone. All therapies were eventually suspended and viro-immunological parameters were monitored over time.

Methods: Cell subpopulations were quantitated by flow cytometry following proper hematological analyses. Viral load and cell-associated vDNA were quantitated by Taqman real-time PCR.

Results: In naïve, central memory and transitional memory CD4+ T cells, auranofin induced both phenotype changes and cell death which were more pronounced in the memory compartment. In the pilot study in vivo, auranofin transiently decreased the cell-associated vDNA reservoir in peripheral blood. When ART was intensified, a sustained decrease in vDNA was observed only in auranofin-treated monkeys but not in controls treated with intensified ART alone. After therapy suspension, only monkeys that had received auranofin showed a deferred and subsequently blunted viral load rebound.

Conclusion: These findings represent a first step towards a remission of primate lentiviral infections.

aBIOQUAL, Inc., Rockville, Maryland

bVGTI-Florida, Port St. Lucie, Florida, USA

cCenci-Bolognetti Foundation, Department of Public Health Sciences, Sapienza University of Rome

dIRCCS San Raffaele Pisana

eCenci-Bolognetti Foundation, Department of Drug Chemistry and Technologies, Sapienza University of Rome

fIstituto Superiore di Sanità, Viale Regina Elena, Rome, Italy.

*Mark G. Lewis and Sandrina DaFonseca contributed equally to the writing of this article.

Correspondence to Dr Andrea Savarino, Department of Infectious, Parasitic and Immune-mediated Diseases, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy. Tel: +39 06 4990 2305; fax: +39 06 4990 3561; e-mail: andrea.savarino@iss.it

Received 21 December, 2010

Revised 21 March, 2011

Accepted 8 April, 2011

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© 2011 Lippincott Williams & Wilkins, Inc.